Short term outcomes of extremely low birth weight infants from a multicenter cohort study in Guangdong of China

With the increase in extremely low birth weight (ELBW) infants, their outcome attracted worldwide attention. However, in China, the related studies are rare. The hospitalized records of ELBW infants discharged from twenty-six neonatal intensive care units in Guangdong Province of China during 2008–2017 were analyzed. A total of 2575 ELBW infants were enrolled and the overall survival rate was 55.11%. From 2008 to 2017, the number of ELBW infants increased rapidly from 91 to 466, and the survival rate improved steadily from 41.76% to 62.02%. Increased survival is closely related to birth weight (BW), regional economic development, and specialized hospital. The incidence of complications was neonatal respiratory distress syndrome (85.2%), oxygen dependency at 28 days (63.7%), retinopathy of prematurity (39.3%), intraventricular hemorrhage (29.4%), necrotizing enterocolitis (12.0%), and periventricular leukomalacia (8.0%). Among the 1156 nonsurvivors, 90.0% of infants died during the neonatal period (≤ 28 days). A total of 768 ELBW infants died after treatment withdrawal, for reasons of economic and/or poor outcome. The number of ELBW infants is increasing in Guangdong Province of China, and the overall survival rate is improving steadily.

www.nature.com/scientificreports/ With the increase in extremely low birth weight (ELBW) infants, their outcome attracted worldwide attention. However, in China, the related studies are rare. The hospitalized records of ELBW infants discharged from twenty-six neonatal intensive care units in Guangdong Province of China during 2008-2017 were analyzed. A total of 2575 ELBW infants were enrolled and the overall survival rate was 55.11%. From 2008 to 2017, the number of ELBW infants increased rapidly from 91 to 466, and the survival rate improved steadily from 41.76% to 62.02%. Increased survival is closely related to birth weight (BW), regional economic development, and specialized hospital. The incidence of complications was neonatal respiratory distress syndrome (85.2%), oxygen dependency at 28 days (63.7%), retinopathy of prematurity (39.3%), intraventricular hemorrhage (29.4%), necrotizing enterocolitis (12.0%), and periventricular leukomalacia (8.0%). Among the 1156 nonsurvivors, 90.0% of infants died during the neonatal period (≤ 28 days). A total of 768 ELBW infants died after treatment withdrawal, for reasons of economic and/or poor outcome. The number of ELBW infants is increasing in Guangdong Province of China, and the overall survival rate is improving steadily.
Low birth weight preterm infants have a particularly high risk for morbidity and mortality 1,2 . In recent decades, the outcomes of preterm infants, especially extremely preterm (defined as gestational age [GA] < 28 weeks) and extremely low birth weight (ELBW, defined as birth weight [BW] < 1000 g) infants, have improved worldwide due to the use of antenatal steroids, pulmonary surfactant treatment and advances in perinatal health care, such as neonatal resuscitation, mechanical ventilation and nutritional management [3][4] . However, the mortality and morbidity vary widely across countries or regions. Generally, more improvements have been gained in developed countries or regions, such as the United States 2,5 , the United Kingdom 6 , Japan 7,8 and Singapore 9 . Available data of extremely preterm and ELBW infants are very important for family counseling and clinical practice improvement. Many neonatal networks or collaborative study groups, such as the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) in the United States 5,10 , Canada Neonatal Network (CNN) 11 , Neonatal Research Network of Japan (NRNJ) 8,12 , Etude Epidémiologique sur les Petits Ages Gestationnels (EPIPAGE) in France 13 , and EPICure in the United Kingdom 6,14 , have worked well and continuously monitored the outcomes of these infants. However, in mainland China, a similar national or provincial network has not been established. The outcomes of extremely preterm and ELBW infants observed in a large population remain unclear. Therefore, we initiated a collaborative study group including twenty-six neonatal intensive care units (NICUs) from Guangdong Province of China to perform a multicenter survey of the short-term outcomes at discharge of extremely preterm or ELBW infants from 2008 to 2017. Generally, GA and BW are the two most important indicators of the maturity for preterm infants. In a previous paper, based on GA, the outcomes of extremely preterm infants were summarized and analyzed 15 . Similarly, based on BW, the outcomes of ELBW infants should be demonstrated. In addition, BW was recommended to group the preterm infants by the World Health Organization and had been used in many studies. This study can be helpful for making comparisons with other studies by BW categories and benefit for continuous quality improvement plan.
The outcomes of ELBW infants can be affected by many aspects such as maternal disorders, fetal or neonatal diseases, perinatal and neonatal care etc. The most influential factors for survival may be the equipment in the NICUs and the skills of the personnel who handle the neonates. In this study, we tried to summarize and analyze the demographics of ELBW infants and their mothers; the survival rate variation among discharged years, BW categories (per 100 g) and regions, or between types of discharged hospital; the major complications of BW categories (per 100 g); the survival days (or hours) of the non-survivors, and the causes for care withdrawal.
To clarify the perinatal factors and outcome of ELBW infants, we specifically grouped the ELBW infants based on survival, shown in Table 1. Both the BW and GA in survivor group were greater than nonsurvivor group (p < 0.001). Comparing with the nonsurvivor group, there were fewer infants in the survivor group with Apgar scores ≤ 3 at 1 min and ≤ 3 or 4-7 at 5 min (all p < 0.001). The survivor group had a longer hospital stay and a higher rate of receiving surfactant therapy (p < 0.001), but there was no significant difference in two or more doses of surfactant therapy. Interestingly, increasing percentage of small for gestational age (SGA) infants was found in survivor group. No significant difference in sex existed between the two groups.
Comparing with the nonsurvivor group, the mothers in the survivor group had a higher proportion of antenatal steroid therapy and cesarean section (both p < 0.001), and a lower incidence of cervical incompetence (p < 0.01). Interestingly, the mothers in the survivor group had higher incidences of premature rupture of membranes (PROM) (p < 0.001), fetal distress (p < 0.05) and pregnancy-induced hypertension (PIH) syndrome (p < 0.001). Between the two groups, a similar prevalence was found in the history of pregnancy problems,  (Table 2). Moreover, the proportion of ELBW infants among all discharged preterm infants rose annually from 1.09% in 2008 to 2.62% in 2017 (p < 0.001), and the proportion of ELBW infants among all discharged infants increased annually from 0.27% in 2008 to 0.77% in  Table 1. Demographics of extremely low birth weight (ELBW) infants and the mothers in outcome categories. GA, gestational age; BW, birth weight; SD, standard deviation; IQR, interquartile range; SGA, small for gestational age; OR, odds ratio; CI, confidence intervals; NS, no significant difference. a History of pregnancy problems refers to that the mother had at least one of the histories as follow: spontaneous abortion, induced abortion, stillbirth, preterm birth, ectopic pregnancy, or baby died during neonatal period.  Table 2). There were twenty-two infants weighing less than 500 g at birth, and only one survived. With the increase per 100 g in BW between 500 and 999 g, the number of ELBW infants increased sharply from 52 in the group with BW 500-599 g to 1294 in the group with BW 900-999 g. In the same time, the survival rate rose dramatically from 30.77% in the group with BW 500-599 g to 65.53% in the group with BW 900-999 g (p < 0.001, Table 3). Variations in survival rates among different regional economic development and hospital categories. According to the prosperity of regional economic development, the collaborative NICUs could be divided into three levels. Specifically, Guangzhou and Shenzhen (including eleven NICUs) belonged to the high level, the other cities in the Pearl Delta (including ten NICUs) belonged to the medium level, and the cities outside the Pearl Delta (including five NICUs) belonged to the low level. From the low level to the high level, the overall survival rates increased sharply (p < 0.05, Table 4). Among the twenty-six NICUs involved, seven were in specialist hospitals (maternal and children's hospitals), and the others were in general hospitals. The overall survival rate of ELBW infants in specialist hospitals was higher than that in general hospitals (p < 0.001, Table 4). To further clarify the influencing cofactors to the survival rate of ELBW infants, binary logistic regression model www.nature.com/scientificreports/ was used. And it suggested that BW, GA, discharged year, regional economic development and hospital categories were associated with the survival rate of ELBW infant ( Table 5).

Complications of ELBW infants during hospitalization. The incidences of major complications in
ELBW infants were 85.2% for neonatal respiratory distress syndrome (RDS), 63.7% for oxygen dependency at 28 days, 39.3% for any grade of retinopathy of prematurity (ROP), 29.4% for any grade of intraventricular hemorrhage (IVH), 12.0% for any stage of necrotizing enterocolitis (NEC) and 8.0% for periventricular leukomalacia (PVL). With the increase per 100 g in BW between 500 and 999 g, Chi-square test linear-by-linear association showed a significant decreasing trend in RDS, oxygen dependency at 28 days, ROP ≥ grade 3, IVH (any grade) and IVH ≥ grade III incidence, respectively (all p < 0.001); but this tendency was not found in incidence of ROP (any grade), NEC (any stage and stage ≥ IIb) or PVL (Table 6).  Table 7. The chi-square test showed that there was a significant difference in the distribution of survival days in nonsurvivors between active treatment and treatment withdrawal (p < 0.001).
In this study, 768 ELBW infants died after withdrawal treatment. The potential reasons were summarized and analyzed.

Discussion
The outcome of ELBW infants has gradually attracted worldwide attention in recent decades. Guangdong Province locates in southern China, with a population of more than 100 million and a highly developed economy and industrialization. In this study, we confirmed that the number of ELBW infants increased rapidly from 2008 to 2017 in Guangdong Province. More importantly, the survival rate improved steadily year by year. These data provide useful information to complement the understanding of ELBW infants in developing countries. From the 1990s or 2000s, the number of ELBW infants began to increase in many developed countries [16][17][18] . Similar to the reports from other countries, our study also suggested a significant increase in ELBW infants over the ten years, from 1.09 per 1000 discharged infants in 2008 to 2.62 per 1000 discharged infants in 2017. A 2.4-fold increase was noted. Although this is not a national population-based survey, it can partly reflect the situation of ELBW infants in China.
Although the economy of Guangdong Province is relatively developed, the regional development is still unbalanced. In results of regional comparisons, we found that ELBW infants in economically developed regions had higher survival rates than those in less economically developing regions. This difference within Guangdong Province may be a microcosm in China. China is a multiprovincial country with unbalanced economic development. Hong Kong, a developed modern city neighboring Guangdong Province, reported higher survival rate 21 . In China, specialist hospitals, such as children's hospitals or maternal and children's hospitals, always have better facilities and more favorable policies in neonatal care than general hospitals. As a result, a higher survival rate was noted in the specialist hospitals in our study. A similar phenomenon was found in another multicenter study from China 21 .
Perinatal management is essential for the outcomes of ELBW infants. Many studies have shown that antenatal corticosteroids effectively decrease the mortality of preterm infants and even reduce various complications, such as RDS, NEC, IVH and ROP 22,23 . Although there is still some controversy regarding the side effects 24 , there is a consensus that the advantages of prenatal corticosteroids outweigh the disadvantages 25,26 . Unfortunately, only 49.2% of ELBW infants' mothers received antenatal corticosteroids in our study, but it was 80%-90% in developed countries 10,27,28 . Therefore, this situation urgently needs to change.
Interestingly, numerous studies have shown that PROM and PIH syndrome are high-risk factors for preterm delivery and infant death 29,30 , but our study showed that the incidence of PROM and PIH syndrome in the survivor group was higher than that in the nonsurvivor group. Moreover, cesarean section was more common in the survivor group. A possible explanation is that PROM or PIH syndrome could have been an early warning that attracted the attention of pregnant women and led them go to the hospital for help in time. When they were admitted to the hospital, more active medical care, such as antenatal corticosteroids, cesarean section, neonatal resuscitation and pulmonary surfactant, was given. Nevertheless, the other potential reasons still need to be further studied and analyzed.
ELBW infants are unstable and tend to suffer various complications due to their prematurity. Without active life support, many infants die during the neonatal period, especially in the first 7 days of age, and some die due to critical illnesses despite receiving active treatments. In our study, 90.0% of nonsurviving infants died during the neonatal period, while nearly 68.3% died in the first 7 days, and the majority died after withdrawal treatment ( Table 6). Although withdrawal treatment in these infants is a controversial issue, it truly exists in developing countries because of the high hospital costs as well as the high risk for poor outcome 31 . We can reasonably believe that the survival of ELBW infants will continue to improve with the economic development and medicine advancement in China.
To the best of our knowledge, this study covers the largest population sample and the longest time span involved in studies of ELBW infants in China to date. It provides useful information for family consultation, clinical practice and further research. However, there are obvious limitations in this study. It is not a populationbased or nationwide study. Moreover, the long-term outcomes of ELBW infants are not addressed, and further studies are needed.

Conclusion
In conclusion, this survey presents an overall short-term outcome of ELBW infants in Guangdong Province of China. Both the number and the survival rate of ELBW infants increased annually from 2008 to 2017.

Participating hospitals and study population. The Collaborative Study Group for Extremely Preterm
and Extremely Low Birth Weight Infants was founded with an aim to investigate the prevalence and the shortterm outcomes of extremely preterm and ELBW infants in Guangdong Province, China. To ensure the survey can be performed feasibly and representatively, the enrolled hospitals were strictly selected as the neonatology department must be the Clinical Key Specialty of Guangdong Province or the representative of medical units offering neonatal intensive care in their respective areas. Even more, the regional distribution of these hospitals was also considered. At last, twenty-six hospitals were involved. The Third Affiliated Hospital of Guangzhou Medical University was responsible for coordinating this study.
The ELBW infants discharged from the NICUs of the collaborative hospitals for the first time between Jan 1st, 2008 and Dec 31st, 2017 were eligible for this study. Only the infants with uncompleted hospitalization records were excluded. The unstable infants transferred to other hospitals or discharged after treatment withdrawal were received follow-up visit in out-patient or by telephone during the study.
All methods were carried out in accordance with relevant guidelines and regulations. The study protocol was approved by the Institutional Review Board of the Third Affiliated Hospital of Guangzhou Medical University and by the Ethics Committees of the Third Affiliated Hospital of Guangzhou Medical University. Written informed consent was obtained from the parents at the time of admission. Data collection. The study protocol was fully discussed by all members, and a standardized questionnaire for data collection, including maternal and neonatal demographics, treatments and major complications during hospitalization, and outcomes at discharge was designed. The same diagnostic criteria were applied to all enrolled NICUs. The relevant records of all enrolled infants and their mothers were reviewed thoroughly, and a questionnaire was completed carefully. All sheets were sent to the Third Affiliated Hospital of Guangzhou Medi- www.nature.com/scientificreports/ cal University, and the data from each questionnaire were input into the database. To minimize bias among centers and investigators, comprehensive and systematic training was provided to the staff involved in the survey. The data collected by the researchers at each collaborative NICU were supervised and checked by the director of the NICU, who was responsible for quality assurance. The records were also checked for accuracy and completeness by collaborative centers.

Definitions and classifications.
In this survey, surviving infants were defined as neonates who survived to the time of discharge. GA was calculated from the date of the last menstrual period or was determined by fetal ultrasound assessment. SGA was defined as newborns whose birth weight is lower than the 10th percentile of birth weight in infants of the same gender and gestational age. RDS was diagnosed in preterm infants with the onset of respiratory distress shortly after birth and a compatible chest radiograph appearance 32,33 . The criteria utilized in our survey for the diagnosis of NEC and for grading the severity of disease were based on Bell's stage 34 . ROP and the graded standard were defined by the international classification of ROP 35 . IVH and PVL were diagnosed by cranial ultrasonography or magnetic resonance imaging (MRI). The Papile grading system was used to grade IVH 36 , and PVL was defined as degeneration of white matter adjacent to the cerebral ventricles following cerebral hypoxia or brain ischemia 37 . Due to the definition of BPD remained inconsistent, we directly descripted and calculated the infants with "oxygen dependency at 28 days".
Statistical analysis. All statistical analyses were performed using SPSS 18.0 for Windows (IBM, Armonk, NY, USA). Continuous variables were presented as the mean ± standard deviation (SD) or as median and interquartile range (IQR) according to the distributions. Categorical variables were presented as counts and percentages. To compare the variation between two groups, t-tests or Mann-Whitney tests were used in continuous variables; while Pearson's Chi-square test was used in categorical variables and presented with odds ratio (OR) and 95% confidence intervals (CI). In addition, Chi-square tests linear-by-linear association were used to compare the survival rates among discharged years, BW categories (per 100 g), regions and the major complication among BW categories (per 100 g), respectively. To further clarify the influencing cofactors (

Ethics declarations. Data collection was approved by the Institutional Review Board of the Third Affiliated
Hospital of Guangzhou Medical University. Written informed consent was obtained from the parents at the time of admission.

Data availability
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. www.nature.com/scientificreports/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.